The American Cancer Society estimates that 23,380 brain and spinal cord tumors will be diagnosed in the United States in 2014. Most brain tumor treatments involve radiation and chemotherapy, which cause serious adverse effects. For example, survivors of medulloblastoma, the most common malignant brain tumor in children, typically have profound neurocognitive deficits due to radiation treatment. However, the development of new drugs is a costly, time-consuming process; only one in ten thousand drug candidates makes it to market, taking fifteen years and one billion dollars to develop. Although continuous progress has been made in developing site-specific nanocarriers, it remains challenging to achieve successful drug treatment of brain tumors without side effect due to the defense of the blood-brain barrier (BBB) and the lack of site-specific nanocarriers stable in circulation. However, most in vitro models of the BBB lack simultaneous integration of vital features including the direct cell interactions. The overall goal of this study is to engineer a new nanocarrier that can cross the BBB, transport a sonic hedgehog (SHH) inhibitor, and target stage-specific embryonic antigen-1 (SSEA-1+) for a SHH-driven brain tumor in the mouse. The BBB-crossing performance of the nanocarrier will be probed in an in vitro microchip model of the BBB, and the targeted delivery and inhibiting efficacy will be examined in an SmoA1/Math1-GFP mouse model of SHH-type medulloblastoma. The engineered nanocarriers will combine the characteristics of high-density lipoprotein (HDL) and lipid-polymer nanoparticles. HDL, a natural nanoparticle transporting lipids with inherent stability in circulation, can traverse the BBB and performs a wide variety of critica functions in the periphery and CNS. PLGA is a FDA approved polymer that provides high drug-loading capacity and slow release of incorporated drug contents. As proof of concept, we will create a new HDL-PLGA nanocarrier that can transport a sonic hedgehog (SHH) inhibitor and target a progenitor cell (SSEA-1+) for a SHH-driven brain tumor in the mouse. BBB-crossing capability of engineered nanocarriers will be examined in an in vitro microchip model of the BBB. The targeted delivery and treating efficacy will be investigated in the SmoA1/Math1-GFP mouse model of SHH-type medulloblastoma. The successful outcomes of this project will demonstrate advanced approaches to the development of new BBB- crossing nanocarriers and in vitro model BBB systems for treating MB and other brain tumors. The nanocarrier targeting model proposed is to test the proof of concept in vivo so may be limited in human translation due to SSEA-1/CD15 being present on blood cells. For our long-term goal of its translation to human clinical studies, at the final stage in Year 2, we will test additional human tumor-specific targeting molecules in this in vitro model for forthcoming R01 application based on these R21 results.
Radiation and chemotherapies of brain tumors lead to adverse effects, getting associated with enormous health care costs. The proposed work will provide the unique approach for the development of a new drug delivery platform and its screening in a more physiologically relevant in vitro model of the blood brain barrier for the detection and treatment of medulloblastoma, the most common malignant brain tumor in children. Advanced screening and treatment and potential derivatives will potentially improve human health and reduce overall costs associated with medulloblastoma and other brain tumors.
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